This is a reentry grant proposal being submitted by an investigator who has undergone Fogarty International Center (FIC)-supported training at the University of California, Berkeley in molecular epidemiology of viral hepatitis. The study will focus on hepatitis C in Prague, Czech Republic. Hepatitis C is a major emerging infectious disease problem in Central and Eastern Europe, especially among young adults who engage in injection drug use (IDU) practice. IDU practice itself has become an epidemic in the last 10 years in Prague, Czech Republic. We wish to take advantage of this epidemic to characterize the natural history, clinical response to therapy, and epidemiology of hepatitis C in Prague. One unique feature of the current hepatitis C epidemic in Prague is that the hepatitis C viral (HCV) subtype diversity is limited, compared to those cities in the US or Western Europe, where IDU has been in practice for a much longer time. Hence, we wish to determine if any sets of viral strain types can be shown to be associated with adverse clinical outcome and response to antiviral therapy. To do so, we plan to 1) compare prospectively HCV genotype and subtype distribution, and evolution of the viral subtypes among cohorts of IDU and non-IDU subjects undergoing treatment for HCV infection in Prague, and determine if such characteristics are associated with certain treatment outcomes; 2) study the natural history of the HCV epidemic among untreated IDU populations for viral subtype distribution, evolution, and clinical outcomes among newly infected subjects in Czech Republic; and 3) create a registry of a database related to viral strain type, patient clinical characteristics, and therapeutic response rates that may be used to evaluate the long-term consequences of HCV infection (cirrhosis, hepatocellular carcinoma) for future use. In the process, we wish to learn about the epidemiology of hepatitis C in Prague and provide new data that may be ultimately used for designing better intervention strategies, including the identification of new antiviral drug targets and HCV vaccine candidates. We also believe that what we learn in Prague will have relevance to other regions in Central and Eastern Europe, including Russia where similar epidemics of IDU are occurring.